Morpholino phenyl carbamates and production thereof



ilnie States Patent MORPHOLINO PHENYL CARBAMATES AND PRODUCTION THEREOF Pierre Chabrier de Lassaunire, Paris, France, assignor to Les Laboratoires Dausse (Socit Anonyme), Paris, France, a French company No Drawing. Application February 2, 1956 Serial No. 563,139

Claims priority, application France February 5, 1955 8 Claims. (Cl. 260247.2)

This invention relates to phenolic organic compounds and particularly to phenyl carbamates, tertiary amino alkoxy phenylamines, tertiary amino alkoxy nitro benzenes, and tertiary amino alkoxy phenyl carbamates, and to processes for the production thereof.

A number of phenyl carbamates having a phenolic hydroxy group in the ortho position or the para position of the benzene nucleus are already known. In particular the ethyl ester of para hydroxy phenyl carbamic (or para hydroxy carbanilic) acid has already been described, and the corresponding methyl, propyl, butyl, isobutyl and isoamyl esters have been mentioned without any description of the production and properties thereof. Methyl, ethyl, propyl, isopropyl, butyl, isobutyl and isoamyl esters of ortho hydroxy phenyl carbamic acid have also been described.

It has now been found that certain tertiary-amino alkyl ethers of the above mentioned phenolic compounds, and other phenolic compounds of the same type having groups of higher molecular weight linked to the carboxy group, are valuable local anaesthetics. Amongst such tertiary amino alkyl ethers, some of them in the form of hydrochlorides show an activity from to 40 times greater than that of cocaine, and a toxicity 2.5 times lower than that of cocaine.

It is an object of this invention to provide a new class of organic compounds being tertiary amino alkoxy phenyl carbamates which have a very valuable utility as anaesthetics. A further object is to provide organic compounds which have a valuable utility in being readily convertible to said carbamates. A still further object is to provide processes for the production of all the said compounds.

According to the present invention there is provided a new class of organic compounds of the general formula YOU where X is a substituent in one of the ortho and para positions to the OY group and is selected from the class consisting of nitro, amino and carbamic acid ester groups, Y is a substituent selected from the class consisting of the hydrogen atom and groupings of the structure Rl 2),.N \R2/ where n is at least 2 and at most 3 and the residue is selected from the class consisting of diethylarnino, morpholino and piperidino groups, and the groupings X and Y contain between them at least 7 carbon atoms.

According to a main feature of this invention, there are provided alkyl and aralkyl esters of ortho and para ter- 2,824,872 Patented Feb. 25, 19 5 8 "ice tiary amino alkoxy phenyl carbamic acid corresponding to the general Formula I in which n and have the meanings assigned to them above and R represents an alkyl or aralkyl group, preferably a hydrocarbon radical having from 1 to 14 carbon atoms and selected from the class consisting of alkyl groups, benzyl groups and phenyl ethyl group, and the acid addition compounds e. g. the hydrochlorides, thereof.

Among the compounds just defined, the alkyl para and ortho tertiary amino alkoxy phenyl carbamates, in which the alkyl group R has 6 to 8 carbon atoms in a straight chain, and the acid addition salts thereof, e. g. hydrochlorides, are particularly important because they are very acid ,G-diethylamino ethylamide) while the toxicity thereof (average fatal dose 45 mg. per kg.) is about 4.5 times less than that of Cinchocaine and 2.5 times less than that of cocaine. The corresponding fi-diethylamino ethoxy phenyl carbamates in which the ester radical contains 6 to 8 carbon atoms are also especially valuable, especially at higher dosages.

Likewise n-heptyl and n-octyl ortho tertiary amino ethoxy phenyl carbamates and the acid addition salts thereof, e. g. hydrochlorides, more particularly those in which the tertiary amino group is a diethylarnino, morpholino or piperidino group, are distinguished by a high surface, local anaesthetic potency.

n-Heptyl para tertiary amino propyloxy phenyl carbamates and their salts, e. g. hydrochlorides are also valuable compounds as surface local anaesthetics; among them, n-heptyl para y-morpholino propyloxy phenyl carbamate hydrochloride has a particularly high anaesthetic potency.

Propyl p-morpholino-ethoxy phenyl carbamate hydrochloride is of a high interest inasmuch as although being weakly active as a surface, local anaesthetic, it shows a very great conduction (trunkal) anaesthetic activity, specifically one which is twice that of procaine which at this time is one of the best and more commonly employed conduction anaesthetics. It is to be noted that while the hydrochlorides are convenient for use by reason of their water-solubility, the bases of which said hydrochlorides are salts exhibit the same local anaesthetic properties and being soluble in fats may be employed for example as oil solutions thereof. When in this specification reference is made to acid addition salts, of which the hydrochlorides are merely the preferred examples, the salts may be derived from any acids which afford a therapeutically acceptable anion.

' Although the foregoing refers primarily to compounds in which R contains up to 8 carbon atoms, the invention 'drochlorides, meresf fare' coinpounds within 'the,

"'p'rbvias higher homologues of those compounds,

i.- e.',"alkyl para tertiary amino alkoxy phenyl carbamates (or carbanilates) corresponding to Formula I but whereinR stands for an alkylgrpup having from9 to 14 carbon: atoms, and acid addition products, particular 1y hydrochlorides, of such compounds such higher homo- 'logues have acceptable anaesthetic activity.

In accordance with a furtlieras'pect of this invention,

a process for the production of compounds of Formula I, comprises condensing a tertiary'arnino'alkyl halide of general Formula II T 7 a a I a where Hal is a halogen atom and the'other symbols have the meanings assigned tothem above, with an alkyl or aralkyl ortho or para hydroxy phenyl carbamate of the gene'r'alFormula III where R has the meaning assigned to it above, in the' presence of an agent capable of binding the halide whichis split outin the reaction. t g 1 Preferably the reaction is carried out atianelevated temperature in an anhydrous alcoholic medium contain hydrogen hydrochlorides' thereof are compounds capable ofgbeing obtained in crystalline form. However the free bases can be isolated if desired .by removing the solvent from an ether solution thereof. H A The compounds of general Formula III, i. e. the alkyl esters of 'ortho and pafafhydroxy phenyl carb'amic acids having from 5 to 8 carbon atoms in the alkyl group, the ben zyl and phenyl ethyl esters of ortho and para hydro'xy ph'enyl carbamic acids, and the'alkyl esters ofpara bon atoms in the alkyl groups are compounds within the scope of thefgeneral formula fir'sts'et forth as is indi dated above have valuable utility inithe production compounds of Formulal.

Theihydroxy phenyl carbamic acid estersof Formula V IIIemployed as'starting materials in the productionof 'comPQunds'of Formulail may'fbe obtained by reacting 'an alkyl or aralkyl 'chlorofo'rmate of the .formula Cl I COQR, where'R hasthe meaning assigned to it aboye, with ortho or para amino phenol, preferably inan inert,

anhydrous, organic solvent, e. g. acetone, ether'oi befi-,

'zene. V ,Ina fnrther'as'pect oi the present inventionc'o'mpoufids of general Formula ,I are obtained by reacting acorness, for producing the compoundsof the formulagfirstset forth in whichX is an NH group comprises subjecting a 7 compound oi the said 'formula'where X is an NO 'group toreduction of that group, preferably'by catalytic hydrogenation. Preferably,hydrogenation is eff t d in the cold at superatmospheric pressure; of hydrogen Pin the presence of a e'atalyst tefg'. palladium, platinum" or the like).

, inearprssiaonipugi ds bfthe formula firstlset forth in whicliX is "nitro, asv'vell' as'the salts, particularly the hydrochlorides thereof are compounds within the scope V of theip'resent invention and have specific; utihtyi as ntermediates in the production of compounds ofFormula I,

as, just set forth xT he said compounds are obtained in.

accordance with 'this invention, by reacting 'an 'or thio 'or para nitro phenol with j a,tertia ry aminof alkyl halide, preferably chloride, in the presence of sodium allcoxide; it s desirable to work inethanol medium.

The water-soluble salts of ethers corresponding to Formula I wherein R'h'as from to 8 carbon atoms, troth ,7 in solution, and have additional utility in various indus-= tries as capillary-active compounds. Furthermore, the

1 others may also be employed'for the synthesis of other.

' r 1 'Hexyl chlorioforrnate (16.5 g., i.-.e. 0.1 mol)- was added compounds'such as halogenalk yla tes. The'following examples will serve to illustrate vention butare not tobe regarded as limiting it in any way. V

' EXAMPLE I Hexyl 1mm 'hydroxyphenyl .carbamate' 7 to paraaminophenol (21.8 g.; i. e. 0.2 m 1 dissolved in:

anhydrous acetone (300 ml);

'hydr oxy'phenyl carbamic acids having froml9 to:I4-car Thesolution'washeated torefiux on a wateribath'for '1 hour and then, cooled, and .para amino phenol hydro chloridewhich separated during the reaction was filtered OE and repeatedly washediwithf anhydrous'. acetone.

Aeetonewas distilledfrom the'filtrate, and thc'solid residue triturated in 10. percentzhydrochloric acid (50 .ml.),;filtere'd off, washed with water repeatedly, and dried 7 over; phosphorus pentoxide. r

, Hexyl para hydroxyphenyl carbamate."( 23:g.; yield 7 97 percent) was obtained as a crystallised, g'reyish substance P. ;1-15. C.; aftertworecrystallisations from 50 .percent alcoh'ol the melting point rose to ll8 'C.; the

Icompound was a white substance. insoluble in water but a very soluble in alcoholxand'acetone EXAMPLE II 1 Hexyl p-te-dietlzylaininmethoxylphenyl c'arbirrriate hid'fi V chloride Hexyl para hydroxyphenyl carbamate (111.9: g.,' i. e., 0.05 mol) obtained according tol'Example I was dissolved in a'sodium ethoxide solution containing sodium (L ;g., i. e., 0.0 5rnol) in absolute alcohol ml"), Betarefiiii ona weter bathiforfl hour. a

pound of the formula first set forth wherein Xis-fan'iainino (NI-I groupflwith an alkylichloroformate'hayingffoin, V s V l to '14 carbon atoms in the alkyl group'onwithibe'uiyl I r. phenyl ethyl "chloroformate, V preferably-inf anganhyldron'siinert, organic mediumj in this way hydro'ehlorides 'of compounds corresponding to Formula I 'ar'e dir'eetly obtained.

Compounds of the general formula fi set in which Xisjan amino :group-and accordingly Y contains ,atleast'Tcarbon atoms, as well as salts, particularly hy of the present invention and haye utility infthe 'r'odlietiof' at ompnnds;ofge iefalfl formula' r fjust; s'etQforthQ 111 astill' further 'aspect' ofthe-p're'sent invention," a proe:

waslid wilh afiliydreusether repeatedly, andjtheri dried' 7' V The miir'turewas allowedto .poolg'precipitatedsodium chloride was filtered off, and washed with absolute alcohol repeatedly,; the washing alcohol was added to the filtrate and the'n'alcohol was removed by distillation' on awater 1' bath.

The oily residue wastalcenup in anhydrous1ether 't 2 ml.), andthe ethersolution filtered to' remove therefrom I a small amount of an ether-insoluble compounds A clear,

(B-diethylamino-ethoxy)'phenyl carbamate;

ether filtrate wasobtained, which contained n-hexyl para- With a view" to converting the base. into hydrochloride j thereof,.a stream of'dry hydrogen chloride. was passed l o" ethyl chloride. (7.5 g.,, i. eJ OQQS mol; plus nt. xcess) ..was added nd the heatedito' 5 over phosphorus pentoxide. The product (14.4 g.; yield 77.4 percent) had a melting point of 144 C. which after one recrystallisation from alcohol rose to 145 C.

The hydrochloride was a white compound, very soluble in water, little soluble in cold alcohol but very soluble in hot alcohol, and insoluble in ether.

EXAMPLE III 1-18- morpholino-ethoxy 4-nitro benzene p-Morpholinyl ethyl chloride (164 g., i. e. 1 mol plus 10 percent excess) was added to p-nitro phenol (139 g., i. e. 1 mol) dissolved in a sodium ethoxide solution containing sodium (23 g., i. e. 1 mol) and absolute alcohol 1200 ml.).

The mixture was heated to reflux for 1 hour, and precipitated sodium chloride was filtered OE and washed repeatedly with alcohol.

The filtrate (to which washing liquids were added) was left in an ice-chest.

l-fi-morpholino-ethoxy 4-nitro benzene which separated out was filtered E, washed with alcohol and then dried. There was thus obtained a crystalline, yellow compound (199 g.) having a melting point of 89 C. The hydrochloride of that compound had a melting point of 199 C.

EXAMPLE IV Para morpholino-ethoxy aniline l-fl-morpholino-ethoxy 4-nitro benzene (50.4 g., i. e. 0.2 mol) prepared according to Example 111 was suspended in absolute alcohol (200 ml.), a percent palladium catalyst g.) was added to the suspension, and cold hydrogenation was effected under an initial pressure of atmospheres.

Upon completion of the hydrogenation process (when the theoretical amount of hydrogen had been absorbed), the catalyst was filtered oif, the alcohol removed from the filtrate and the residue distilled in a high vacuum. An amino compound distilling at 165-167" C. under a pressure of 0.4 mm. of mercury (37.9 g.) was thus collected, as a colourless liquid which set on cooling to a White, crystalline mass, darkening in air, M. P. 73 C.

The corresponding hydrochloride had a melting point of 176 C.

EXAMPLE V Heptyl para fi-morpholino-ethoxy phenyl carbamate hydrochloria'e l-fi-morpholino-ethoxy 4-amino benzene (44.1 g., i. e.

0.2 mol), prepared according to Example IV, was dissolved in anhydrous methyl ethyl ketone (200 1111.), and the solution was gradually added while stirring to heptyl chloroformate (35.6 g., i. e. 0.2 mol) dissolved in anhydrous methyl ethyl ketone 1111.). An exothermic reaction occurred which was moderated by cooling the mixture in a water-bath.

The compound separated out immediately as a white precipitate.

The mixture was left overnight at room temperature, and heptyl para-,B-morpholino ethoxy phenyl carbamate was filtered off, washed three times with anhydrous methyl ethyl ketone and then dried in vacuo.

After one recrystallisation from anhydrous methyl ethyl ketone over animal charcoal, a crystalline, white compound (60 g.; yield 75%) having a melting point of 152 C. was obtained.

Alkyl and aralkyl ortho tertiary amino alkoxy phenyl carbamate hydrochlorides may be prepared from ortho amino phenol instead of para amino phenol via alkyl and aralkyl ortho hydroxy phenyl carbamates exactly in accordance with the processes described in Examples I and II. a

The foregoing five examples illustrate, for typical specific'ca'ses, production processes having a general scope, as will be apparent from the following:

E A. Working in accordance with the technique described in Example I, there were prepared the alkyl and aralkyl para and ortho hydroxy phenyl carbamates listed in the following Table I (the melting points mentioned in the tables were determined on a Maquenne block) and corresponding to the general formula TABLE I Melting Yield, Position of OH R. point percent (degrees C.)

CH: 118 CzHs 127 97 11-GaH1 104 84 11-04Ho 108 98 1-C4Hu 119 84 Ill-05H 110 82 D-C5H13 118 97 Ill-C7Hr5 93 n-CsHn 117 83 11-C10H2r 122 86 n-C H29 124 51 Co zs--C.Hz 84 CaH CH2-CH2 156 95 C2H5 88. 5 92 DC H9 89 94 11-CaH1s 57-58 89 lit-07H 55 97 n-CsHn 59 82 CuH5-CH2 117 90 Generally speaking, the ortho and para hydroxy phenyl carbamates are white, crystalline compounds: the lower members of the series are only slightly soluble in cold .a mixture of water and alcohol in varying proportions TABLE II Yield, percent diethylaminm...

Most hydrochlorides listed in the above table are soluble in water but insoluble in ether, and it is generally desirable to recrystallise them from ethyl acetate.

The corresponding bases are uncrystallisable, undistillable oils.

C. Working in accordance with the technique dc scribed in Example 11 or Example V, there were probut insoluble in water, even "hot water.

' V V {7t 7 duced" the alkyl and taralkyl p tertiary-amino-alkoxy phenyl 'carbamate hydrochlorides listed in the following Table and corresponding to the generallfornmla TABLElII stances: having well-defined ,rnelting pointsfthey (are. soluble inwatenonly slightly: soluble' incold methyl or.

ethyl alcohol but v 'Melting point Yield (method .5}

example)- Percent 1 V dletgylamino.'

NNNJ

wwaowuwkowmww w Some of fthej alkyl' and aralkyl p'-tertiary-an1inoa1koxy' phenyl carbamates are's olld, white compounds capable of being recrystallised from mixture's'of water and-al- V J coholt in varying proportions; and having relatively low ,nrelting point (as apparent from the table); others are uncrystallisable oils. All are soluble in alcohol and ether The hydrochlorides thereof are 7 white, crystalline conipounds, having higher 'rnelting points than the correspending bases, soluble inlwater'bu t insoluble in ether.-

1). Working in accordance 'with the technique described in Example 'III, Where were produced the p-tertiary-amino' alko'xy' nitro' benz'nes listed in the following Table IV and corresponding to the general formula V i 7 stor-ma ma nitro tei'tiary-aminoethoiiy'henzenes crystal1ine5'jelloxy icompoiinds-liaying low melting 50 V V 7 and also the hydrochlorides thereof. i r

- LE'Y 55;} M A r o t t R1 a Hydro-t V t a Yield, chlorid -N 7' n Meltingi I percent :Melting 1 point i Boiling point ;poi nt(de- 7 R2 (degrees eesQ) V .gr q Q-J diethylaininol. 2 115551369 05 a 51,; morpholino 2' 73 165167,/0.4.mm 85' 7 Do 3 49 180181/0.8'mm: 87 pip eridinornn 2 65. ,145-1476 10,i)9,mm '90;

7 r r O aN--CaH4O( H2) -N V V V R: 7'

; TABLE IV V Hydro- V t B1 c Ease, chloride,

I ,Melting 'Yield, 'Melting; N- 7, 1r point (degrees Percent point t v 'r 7 grees 5, L

as hmatic; 2 164 morphblino" 2' 199 oi- 3 -plpegidtum; 2'

' E. Working in accordance with the technique-Q de-l scribed in Example IV, therewere produced the p:(tertiary-amino-alkoxy) amino-b'enzenes listed in the following table and correspondingto the {general fc zrrtu la.v

Most of, the para ltertiary i alkoziyjanilines r K crystalline, white" compounds, or colourless: oils apable of being distilled im a .highwacunm; they: are soluble. ,in'

l water; alcohol, ether, and acetone 1"'[he hydrochlorides I thereof are crystalline, white substanceswhichfbecoine brown i111 air, and are" soluble. in11;v\iater, only; slightly,

soluble cold alcohol b'ut" yerysoluble inl hot319M101; The'basic etheifs corresponding to herewith general jForrnulat-lfcan be'eonverteditg,ssaltsi'of acid ther than hydrochloric acid, iaar'ticularly. othei fiacid ready been proposed 1 or mPl t Me 1, oyedi f o igpr od n fjaci 7 addition salts from anaesthetic bases. Such other salts also form a part of this invention.

I claim:

1. A compound selected from the class consisting of compounds of the general formula Q o N- onon-o NrLoooR Where n is at least 2 and at most 3, and R is an alkyl group having from 1 to 14 carbon atoms, and the acid addition salts thereof.

2. A compound according to claim 1 wherein R is an alkyl group of 6 to 8 carbon atoms.

3. A compound selected from the class consisting of n-heptyl para fl-morpholino ethoxy phenyl carbamate and the hydrochloride thereof.

4. A compound selected from the class consisting of propyl para B-morpholino ethoxy phenyl caroamate and the hydrochloride thereof.

5. A process for the production of basic phenyl carbamates, wherein a morpholino alkly halide where n is at least 2 and at most 3, is reacted with a compound of the formula where R is an alkyl group having from 1 to 14 carbon atoms, in the presence of an agent capable of binding the hydrogen halide formed in the reaction.

6. A process as claimed in claim 5, wherein the reaction is carried out at an elevated temperature in an anhydrous alcoholic medium containing an alkali metal.

7. A process as claimed in claim 5, wherein the reactants are heated to reflux in an ethanol solution of sodium ethoxide, the sodium halide thus formed is separated, and alcohol is removed from the reaction solution.

8. A process as claimed in claim 5, wherein the reaction product, after having been isolated, is dissolved in ether, and dry hydrogen chloride is passed through the ether solution to produce a hydrochloride.

References Cited in the file of this patent UNITED STATES PATENTS Weissberger May 8, 1951 OTHER REFERENCES 

1. A COMPOUND SELECTED FROM THE CLASS CONSISTING OF COMPOUNDS OF THE GENERAL FORMULA 